CA1107647A - Stable secretin composition, process for its preparation and its use - Google Patents
Stable secretin composition, process for its preparation and its useInfo
- Publication number
- CA1107647A CA1107647A CA318,777A CA318777A CA1107647A CA 1107647 A CA1107647 A CA 1107647A CA 318777 A CA318777 A CA 318777A CA 1107647 A CA1107647 A CA 1107647A
- Authority
- CA
- Canada
- Prior art keywords
- secretin
- composition
- stable
- added
- chemical equivalent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
STABLE SECRETIN COMPOSITION, PROCESS FOR ITS
PREPARATION AND ITS USE
Abstract of the disclosure:
A stable secretin composition showing a pH value of 3.0, a process for its preparation and its use for the treatment of acute gastric haemorrhages, Ulcus duodeni, Ulcus ventriculi, the Zollinger-Ellison syndrome, muco-viscidosis and reflux oesophagitis, for the prophylaxis of stress ulcera and the diagnosis of the pancreatic function and of Ulcus duodeni.
PREPARATION AND ITS USE
Abstract of the disclosure:
A stable secretin composition showing a pH value of 3.0, a process for its preparation and its use for the treatment of acute gastric haemorrhages, Ulcus duodeni, Ulcus ventriculi, the Zollinger-Ellison syndrome, muco-viscidosis and reflux oesophagitis, for the prophylaxis of stress ulcera and the diagnosis of the pancreatic function and of Ulcus duodeni.
Description
7~7
- 2 - HOE 77/F 2~3 The present invention relates to a stable secretin compositlon, a process for its preparation and its use.
The invention provides a stable secretin composi-tion for injection purposes, a process for its preparation and its use as medicament, prophylactic and diagnostic agent.
:Secretin is a heptacosipeptidamide (Eur,J.Biochem, 15, 513 (19'70)) which is formed in the duodenum and ~lhich, besides showing other properties, above all stimulates the hydrogenocarbonate production of the pancreas and inhibits the action of gastrin, It is therefore appropriate for the diagnosis and therapy of diseases of the digestive tralt, In the above and the following description the term secretin inclucles the physiologically tolerable salts.
According to the invention there is used natural as ~ell as synthetic secretin.
It has already been described that secretin is very unstable and rapidly loses its biological effect especial-ly in solution at room temperature (Methods in Investiga-tive and Diagnostic Endocrinology, vol, 2B, page 1067, North Holland Publishing Co,, Amsterdam, London 1973), This is why secretin is stored in a lyophilized form and is dissolved not until shortly before its use.
2~Since secretin is frequently administered in very small amounts (for example, from 0.025 to 0,2 mg, which corresponds to about 100 to aoo cu (cu rneaning clinical unlt)), it is advantageous to add a vehicle substance to 29 the secretin solution prior to lyophili~ation, in ordcr to , ~
76~7
The invention provides a stable secretin composi-tion for injection purposes, a process for its preparation and its use as medicament, prophylactic and diagnostic agent.
:Secretin is a heptacosipeptidamide (Eur,J.Biochem, 15, 513 (19'70)) which is formed in the duodenum and ~lhich, besides showing other properties, above all stimulates the hydrogenocarbonate production of the pancreas and inhibits the action of gastrin, It is therefore appropriate for the diagnosis and therapy of diseases of the digestive tralt, In the above and the following description the term secretin inclucles the physiologically tolerable salts.
According to the invention there is used natural as ~ell as synthetic secretin.
It has already been described that secretin is very unstable and rapidly loses its biological effect especial-ly in solution at room temperature (Methods in Investiga-tive and Diagnostic Endocrinology, vol, 2B, page 1067, North Holland Publishing Co,, Amsterdam, London 1973), This is why secretin is stored in a lyophilized form and is dissolved not until shortly before its use.
2~Since secretin is frequently administered in very small amounts (for example, from 0.025 to 0,2 mg, which corresponds to about 100 to aoo cu (cu rneaning clinical unlt)), it is advantageous to add a vehicle substance to 29 the secretin solution prior to lyophili~ation, in ordcr to , ~
76~7
- 3 - HOE 77/F 263 avoid the rlsk of dust formation.
It has been known from literature that the carrier substances which are commonly used, such as dextran and mannitol, adversely affect the stabillty of secretln (German Offenlegungsschrift No. 2 323 187). According to the d!ata given in Gastroenterology 57, 767 (1969), cy-steine hydrochloride is suitable as vehicle with a favor-able influence on the stability. However, it is a drawback that the secretin stabilized in this manner cannot be iodized in a radioactive manner any more, which makes it unsuitable for use in radioimmuno-assays. Solubility problems (clouding of the solution) might also arise from a possible oxidation of the easily soluble cysteine to give the sparingly soluble cystine.
In German Offenlegungsschrift No. 2 323 187 different amino acids are tested for their capability of being used as carrier substances in secretin preparations. In this connection it was found that at a pM value of from 4 to
It has been known from literature that the carrier substances which are commonly used, such as dextran and mannitol, adversely affect the stabillty of secretln (German Offenlegungsschrift No. 2 323 187). According to the d!ata given in Gastroenterology 57, 767 (1969), cy-steine hydrochloride is suitable as vehicle with a favor-able influence on the stability. However, it is a drawback that the secretin stabilized in this manner cannot be iodized in a radioactive manner any more, which makes it unsuitable for use in radioimmuno-assays. Solubility problems (clouding of the solution) might also arise from a possible oxidation of the easily soluble cysteine to give the sparingly soluble cystine.
In German Offenlegungsschrift No. 2 323 187 different amino acids are tested for their capability of being used as carrier substances in secretin preparations. In this connection it was found that at a pM value of from 4 to
4.5 alanine proved to be superior to, for example, glycine, threonine or valine and that alanine is thus appropriate as vehicle of stable secretin compositions.
We have now found that the stabillty of secretin com-positions strongly depends on the pH value and the tempe-rature of the solution and that glycine buffered to a pH
of 3 is particularly suitable as carrier substance.
The subject of the present invention is therefore a stable lyophilized secretin composition which has been adjusted with hydrochloric acid to a pM value of 3 and 29 ~hich optionally contains glycine buffered to pH 3 as car-.~ . . .
, ~37~7 - 4 - ~OE 7t/F 263 rier substance.
The invention further provides a process for the pre-paration of a stable lyophilized secretin composition, which comprises adding secretin to an a~ueous solution ad-justed with hydrochloric acid to a pH of 3 and cooled toabout 0 to 10C, the solution optionally containing gly-cine buffered with hydrochloric acid to pH 3, flltering the solution under sterile conditions, filling it into bottles or ampules and lyophilizing it.
In Figure 1 the biological activity of a secretin composition containing 0.1 mg of secretin hydrochloride and 20 mg of glycine as carrier substance has been illu-strated. Curves 1 and 2 not only demonstrate the activity as a function of the pH value of the composition, but also the dependence on temperature. The composition which has been lyophilized only after 68 hours o~ standing at room temperature (curve 2) has lost in activity as compared with the cornposition which has been lyophilized imrnedia-tely (curve 1). The maximum activity is found at a pH
value of 3.
In order to avoid the loss in activity due to in-fluences of temperature, the secretin-containing solution is lyophilized instantly according to the process of the invention, if possible.
With a lower secretin dosage (0.025 mg per ampule) it has been observed that also composltions of a pH value of 3 showed a lower biological effect than was to be expected.
It has been found, however, that these compositions 2g regain their full activity upon adding gelatin partial hy-.
::
, .
' ~ 7~7
We have now found that the stabillty of secretin com-positions strongly depends on the pH value and the tempe-rature of the solution and that glycine buffered to a pH
of 3 is particularly suitable as carrier substance.
The subject of the present invention is therefore a stable lyophilized secretin composition which has been adjusted with hydrochloric acid to a pM value of 3 and 29 ~hich optionally contains glycine buffered to pH 3 as car-.~ . . .
, ~37~7 - 4 - ~OE 7t/F 263 rier substance.
The invention further provides a process for the pre-paration of a stable lyophilized secretin composition, which comprises adding secretin to an a~ueous solution ad-justed with hydrochloric acid to a pH of 3 and cooled toabout 0 to 10C, the solution optionally containing gly-cine buffered with hydrochloric acid to pH 3, flltering the solution under sterile conditions, filling it into bottles or ampules and lyophilizing it.
In Figure 1 the biological activity of a secretin composition containing 0.1 mg of secretin hydrochloride and 20 mg of glycine as carrier substance has been illu-strated. Curves 1 and 2 not only demonstrate the activity as a function of the pH value of the composition, but also the dependence on temperature. The composition which has been lyophilized only after 68 hours o~ standing at room temperature (curve 2) has lost in activity as compared with the cornposition which has been lyophilized imrnedia-tely (curve 1). The maximum activity is found at a pH
value of 3.
In order to avoid the loss in activity due to in-fluences of temperature, the secretin-containing solution is lyophilized instantly according to the process of the invention, if possible.
With a lower secretin dosage (0.025 mg per ampule) it has been observed that also composltions of a pH value of 3 showed a lower biological effect than was to be expected.
It has been found, however, that these compositions 2g regain their full activity upon adding gelatin partial hy-.
::
, .
' ~ 7~7
- 5 - HOE 77/F 263 . ..~
drolysate which is cross~linked via diisocyanates (cf. Ger-man Patents Nos. 1,118,792 and 1,155,134) ((R)Haemaccel), human albumin or human globin. Evidently the result found was not due to a deactivation of the secretin, but was 5 caused by an adsorption of the secretin at the glass sur-face lof the amlpule, which may be prevented andtor undone by adding proteins or protein-like substances.
For this reason compositions having a lower secretin content suitably include the above-mentioned additives.
10 The latter are not required in the case of high-dosage compositions (for example 80o CU and more per ampule).
In order to achieve a protracted action of the secre-tin, the secretin composition of the invention may be mix-ed prior to administration with a depot carrier. As depot 15 carrier there is used preferably a mixture of polyphlore-tin phosphate and gelatin partial hydrolysate cross-linked with diisocyanates (cf. German Patent No. 2,104,344).
Since the secretin compositions are injected, it is ad-vantageous to dissolve the lyophilized product prior to 20 its administration in Aqua pro injectione which contains a physiologically tolerable buffer.
The secretin compositions of the invention are sui-table as diagnostic agents for the pancreatic functlon and for the diagnosis of Ulcus duodeni, as therapeutic agents 25 for Ulcus duodeni, Ulcus ventriculi, stress ulcera, bleed-ings in the gastroduodenal region, reflux oesophagitis, mucoviscidosis and the Zollinger-Ellison syndrome, as well as for the prophylaxis of stress ulcera, for example af~er Zg operations, multiple fractures, burns and septicaemias.
. . , - ,. ,. ; . .
- ..
:: . :~ ..
:
, .
drolysate which is cross~linked via diisocyanates (cf. Ger-man Patents Nos. 1,118,792 and 1,155,134) ((R)Haemaccel), human albumin or human globin. Evidently the result found was not due to a deactivation of the secretin, but was 5 caused by an adsorption of the secretin at the glass sur-face lof the amlpule, which may be prevented andtor undone by adding proteins or protein-like substances.
For this reason compositions having a lower secretin content suitably include the above-mentioned additives.
10 The latter are not required in the case of high-dosage compositions (for example 80o CU and more per ampule).
In order to achieve a protracted action of the secre-tin, the secretin composition of the invention may be mix-ed prior to administration with a depot carrier. As depot 15 carrier there is used preferably a mixture of polyphlore-tin phosphate and gelatin partial hydrolysate cross-linked with diisocyanates (cf. German Patent No. 2,104,344).
Since the secretin compositions are injected, it is ad-vantageous to dissolve the lyophilized product prior to 20 its administration in Aqua pro injectione which contains a physiologically tolerable buffer.
The secretin compositions of the invention are sui-table as diagnostic agents for the pancreatic functlon and for the diagnosis of Ulcus duodeni, as therapeutic agents 25 for Ulcus duodeni, Ulcus ventriculi, stress ulcera, bleed-ings in the gastroduodenal region, reflux oesophagitis, mucoviscidosis and the Zollinger-Ellison syndrome, as well as for the prophylaxis of stress ulcera, for example af~er Zg operations, multiple fractures, burns and septicaemias.
. . , - ,. ,. ; . .
- ..
:: . :~ ..
:
, .
- 6 - HOE 77/F 263 As diagnosti~ agent for the pancreatic function there is preferably used 2 10 ml ampule with 100 CU. The con-tents of the ampule are dissolved in 10 ml of physiolog,cal salt solution and slowly administered intravenously. Also an infusion for this purpose is possible.
~ he secretin composition of the invention is also appropriate for the diagnosis of Ulcus duodeni, for fol-lowing an intracutaneous administration of secretin a positive skin reaction was observed in Ulcus patients and ! 10 test persons who had a duodena]. ulcer in former years.
This observation is therefore employed for diagnosis.
Secretin is administered in this case in doses of from preferably 5 to 10 CU.
Bleedings in the gastroduodenal region are treated with secretin infusions. About 0.5 CU per kilogram of body weight is administered within one hour. The infusion period is as a rule 48 hours. For this purpose, the 200 CU ampule is particularly suitable which lasts for about 4 to 5 hours. It is recommended to prepare a fresh solution every 4 to 5 hours.
In the therapy of Ulcus duodenl and Ulcus ventriculi there is preferably used a depot carrier according to German Patent No. 2,104,344 ~hich maintains the secretin act.ion at the pancreas (hydrogenocarbonate secretion) and at the stomach (gastrin inhibition) for several hours.
For reasons of stability the depot carrier is not admixed to the secretin composition, but is only mixed with secretin immediately ~efore administration. Another rea-29 son for the separate storage of the depot carrier and the 6~7 KOE 77!F 263secretin composition i3 provided by the opportunity of an exact secretin dosing which depends on the weight of the patient. The dose is in this therapy preferably 10 CU
per kilogram of body weight. For this use, for example, a 800 CU ampule is appropriate. The depot carrier and the secretin composition of the invention are dissolved to-gether in 1 ml of bidistilled water and are injected sub-cutaneously. 1 to 2 injections of this depot carrier/se-cretin mixture are administered daily, and the therapy may be prolonged up to 6 weeks. This depot composition may alsol be employed for treating the Zollinger-Ellison syn-drome, mucoviscidosis and reflux oesophagitis, as well as for the prophylaxis of stress ulcera, for example after operations, multiple fractures, burns and septicaernias.
The following Examples serve to illustrate the inven-tion.
E X A M P L E 1:
.
100 CU ampule A solution of 20 g of glycine in 400 ml of water which has been cooled to about 5C is adjusted with 1N HCl to a pH value of 3. To this solution are added 2.5 g of gela-tin partial hydrolysate cross-linked with diisocyanates (Haemaccel(R)) in the form of an about 10 g solution. In this carrier solution 100,000 CU of secretin hydrochloride are dissolved. The mixture is then made up with water to 500 ml. The solution is filtered through an appropriate filter under sterile conditions and is subsequently filled into ampules of 0.5 ml each and lyophili7ed.
.
~v~ 7 - 8 - P.OE_ 7/F
E X A _ P L ~ 2:
100 CU ampule The composition is prepared in a manrler analogous to that of Example 1. Instead of 2.5 g of Haemaccel there is added 1 g of human albumin.
E X A M P L E 3:
2 CU ampule The composition is prepared in a manner analogous to that of Example 1. Instead of 100,000 CU there are added 200,000 CU of secretin llydrochloride.
E X A M P L E 4:
I
200 C_ _ pule I The composition is prepared in a manner analogou,s to that of Example 3. Instead of 2.5 g of Haemaccel there is added of 0.5 g of human globin.
E X A M P L E 5:
800 CU ampule .
The composition is prepared in a manner analogous to that of Example 1. Instead of 100,000 CU there are added 80o,000 CU of secretin hydrochloride. The 2.5 g of ~ae-maccel are not added.
E X A M P L E 6: `
10 CU ampule . . .
The composition is prepared in a manner analogous to that of Example 1. Instead of 100,000 CU there are added 10,000 CU of secretin hydrochloride.
E X A M P L E 7:
. _ . ....
Preparation of the depot carrier 29 3 Grams of polyphloretin phosphate are dissol~ed, while ,~
:, , , ~ - :
:.
-6~7 stirring, in 1N NaOH, and the solution is adjusted to a pH value of 6.8. To this solution there are added 8 g of Haemaccel as a ~0 ~ solution. Subsequently the mixture is made up to 200 ml with distilled water, is filtered un-der sterile conditions and filled into bottles having arolled edge or 2 ~l each and is lyophilized.
:, :"
~;
~ he secretin composition of the invention is also appropriate for the diagnosis of Ulcus duodeni, for fol-lowing an intracutaneous administration of secretin a positive skin reaction was observed in Ulcus patients and ! 10 test persons who had a duodena]. ulcer in former years.
This observation is therefore employed for diagnosis.
Secretin is administered in this case in doses of from preferably 5 to 10 CU.
Bleedings in the gastroduodenal region are treated with secretin infusions. About 0.5 CU per kilogram of body weight is administered within one hour. The infusion period is as a rule 48 hours. For this purpose, the 200 CU ampule is particularly suitable which lasts for about 4 to 5 hours. It is recommended to prepare a fresh solution every 4 to 5 hours.
In the therapy of Ulcus duodenl and Ulcus ventriculi there is preferably used a depot carrier according to German Patent No. 2,104,344 ~hich maintains the secretin act.ion at the pancreas (hydrogenocarbonate secretion) and at the stomach (gastrin inhibition) for several hours.
For reasons of stability the depot carrier is not admixed to the secretin composition, but is only mixed with secretin immediately ~efore administration. Another rea-29 son for the separate storage of the depot carrier and the 6~7 KOE 77!F 263secretin composition i3 provided by the opportunity of an exact secretin dosing which depends on the weight of the patient. The dose is in this therapy preferably 10 CU
per kilogram of body weight. For this use, for example, a 800 CU ampule is appropriate. The depot carrier and the secretin composition of the invention are dissolved to-gether in 1 ml of bidistilled water and are injected sub-cutaneously. 1 to 2 injections of this depot carrier/se-cretin mixture are administered daily, and the therapy may be prolonged up to 6 weeks. This depot composition may alsol be employed for treating the Zollinger-Ellison syn-drome, mucoviscidosis and reflux oesophagitis, as well as for the prophylaxis of stress ulcera, for example after operations, multiple fractures, burns and septicaernias.
The following Examples serve to illustrate the inven-tion.
E X A M P L E 1:
.
100 CU ampule A solution of 20 g of glycine in 400 ml of water which has been cooled to about 5C is adjusted with 1N HCl to a pH value of 3. To this solution are added 2.5 g of gela-tin partial hydrolysate cross-linked with diisocyanates (Haemaccel(R)) in the form of an about 10 g solution. In this carrier solution 100,000 CU of secretin hydrochloride are dissolved. The mixture is then made up with water to 500 ml. The solution is filtered through an appropriate filter under sterile conditions and is subsequently filled into ampules of 0.5 ml each and lyophili7ed.
.
~v~ 7 - 8 - P.OE_ 7/F
E X A _ P L ~ 2:
100 CU ampule The composition is prepared in a manrler analogous to that of Example 1. Instead of 2.5 g of Haemaccel there is added 1 g of human albumin.
E X A M P L E 3:
2 CU ampule The composition is prepared in a manner analogous to that of Example 1. Instead of 100,000 CU there are added 200,000 CU of secretin llydrochloride.
E X A M P L E 4:
I
200 C_ _ pule I The composition is prepared in a manner analogou,s to that of Example 3. Instead of 2.5 g of Haemaccel there is added of 0.5 g of human globin.
E X A M P L E 5:
800 CU ampule .
The composition is prepared in a manner analogous to that of Example 1. Instead of 100,000 CU there are added 80o,000 CU of secretin hydrochloride. The 2.5 g of ~ae-maccel are not added.
E X A M P L E 6: `
10 CU ampule . . .
The composition is prepared in a manner analogous to that of Example 1. Instead of 100,000 CU there are added 10,000 CU of secretin hydrochloride.
E X A M P L E 7:
. _ . ....
Preparation of the depot carrier 29 3 Grams of polyphloretin phosphate are dissol~ed, while ,~
:, , , ~ - :
:.
-6~7 stirring, in 1N NaOH, and the solution is adjusted to a pH value of 6.8. To this solution there are added 8 g of Haemaccel as a ~0 ~ solution. Subsequently the mixture is made up to 200 ml with distilled water, is filtered un-der sterile conditions and filled into bottles having arolled edge or 2 ~l each and is lyophilized.
:, :"
~;
Claims (13)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a stable secretin composition, which shows a pH value of 3.0, in which secretin is added to an aqueous solution which has been adjusted with hydrochloric acid to a pH value of 3 and has been cooled to about 0 to 10°C, the solution is filtered under sterile conditions, filled into bottles or ampules and lyophilized.
2. A stable secretin composition, whenever obtained by a process as claimed in claim 1 or by an obvious chemical equivalent thereof.
3. A process as claimed in claim 1 in which the aqueous solution adjusted to pH 3 contains glycine buffered with hydro-chloric acid to a pH value of 3.
4. A process as claimed in claim 3 in which the glycine is present in an amount of 5 to 50 mg per dosage unit.
5. A stable secretin composition, whenever obtained according to a process as claimed in claim 3 or claim 4 or by an obvious chemical equivalent thereof.
6. A process as claimed in claim 1 in which a gelatin partial hydrolysate cross-linked with a diisocyanate, human albumin or human globin is added to the aqueous solution.
7. A stable secretin composition, whenever obtained by a process as claimed in claim 6 or by an obvious chemical equivalent thereof.
8. A process as claimed in claim 1 in which a depot carrier consisting of a gelatin partial hydrolysate cross-linked with a diisocyanate and polyphloretin phosphate are added to the composition immediately prior to use thereof.
9. A stable secretin composition, whenever obtained according to a process as claimed in claim 8 or by an obvious chemical equivalent thereof.
10. A process as claimed in claim 1 in which secretin hydrochloride, secretin hydrobromide or a mixture thereof is added to the composition.
11. A stable secretin composition, whenever obtained according to a process as claimed in claim 10 or by an obvious chemical equivalent thereof.
12. A process as claimed in claim 1 in which Aqua pro injectione or a physiologically tolerable buffer solution is added to the composition prior to use thereof.
13. A stable secretin composition, whenever obtained according to a process as claimed in claim 12 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772758578 DE2758578A1 (en) | 1977-12-29 | 1977-12-29 | STABLE SECRETARY PREPARATION, METHOD FOR THEIR PRODUCTION AND THEIR USE |
| DEP2758578.0 | 1977-12-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1107647A true CA1107647A (en) | 1981-08-25 |
Family
ID=6027573
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA318,777A Expired CA1107647A (en) | 1977-12-29 | 1978-12-28 | Stable secretin composition, process for its preparation and its use |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0002777A1 (en) |
| JP (1) | JPS5498315A (en) |
| AT (1) | AT363588B (en) |
| AU (1) | AU525114B2 (en) |
| CA (1) | CA1107647A (en) |
| DE (1) | DE2758578A1 (en) |
| ZA (1) | ZA787363B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58162530A (en) * | 1982-03-19 | 1983-09-27 | Eisai Co Ltd | Anticancer agent for cancer caused by gastrin in digestive organ |
| JPH0341033A (en) * | 1989-07-07 | 1991-02-21 | Kyowa Hakko Kogyo Co Ltd | Stable preparation containing motilins |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE396693B (en) * | 1970-02-16 | 1977-10-03 | Paulsen Fredrik | METHOD OF PREPARING COMPLEX OF SYNTHETIC CORTICOTROPINE WITH ENHANCED AND EXTENDED EFFECT |
| DE2104344B2 (en) * | 1971-01-30 | 1975-08-21 | Hoechst Ag, 6000 Frankfurt | Protracted secretin preparation |
| JPS5029005B2 (en) * | 1972-05-08 | 1975-09-19 | ||
| DE2615229C2 (en) * | 1976-04-08 | 1984-05-24 | Hoechst Ag, 6230 Frankfurt | Process for the production and purification of secretin |
-
1977
- 1977-12-29 DE DE19772758578 patent/DE2758578A1/en not_active Withdrawn
-
1978
- 1978-12-19 EP EP78101753A patent/EP0002777A1/en not_active Withdrawn
- 1978-12-22 AU AU42850/78A patent/AU525114B2/en not_active Expired
- 1978-12-28 ZA ZA00787363A patent/ZA787363B/en unknown
- 1978-12-28 JP JP16598278A patent/JPS5498315A/en active Pending
- 1978-12-28 AT AT0932778A patent/AT363588B/en not_active IP Right Cessation
- 1978-12-28 CA CA318,777A patent/CA1107647A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5498315A (en) | 1979-08-03 |
| AT363588B (en) | 1981-08-10 |
| AU525114B2 (en) | 1982-10-21 |
| EP0002777A1 (en) | 1979-07-11 |
| AU4285078A (en) | 1979-07-05 |
| ZA787363B (en) | 1979-12-27 |
| DE2758578A1 (en) | 1979-07-05 |
| ATA932778A (en) | 1981-01-15 |
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